The biological response to peripheral nerve injury is highly intricate and comprises a synchronized sequence of cellular and molecular processes, including Wallerian degeneration, Schwann cell stimulation, macrophage-dependent debris removal, vascularization, extracellular matrix remodeling, and axonal regeneration. Successful recovery relies not only on the inherent regenerative capability of peripheral nerves but also on the reestablishment of a permissive niche facilitating neural healing. In the mandibular canal, however, regeneration may be impaired by distinct anatomical limitations. Edema, vascular inadequacy, inflammation, and fibrosis can compromise axonal regrowth and contribute to persistent neurosensory disturbance. Consequently, functional recovery after IAN injury is largely unpredictable, underscoring the need for therapeutic strategies that actively facilitate regeneration rather than merely attenuating symptoms.

Contemporary management approaches for IAN injury remain mainly supportive. Corticosteroids are mostly used during the acute phase to alleviate edema and inflammation, while microsurgical interventions, pharmacologic neuroregulators, and local anesthetics are administered in some cases. Although these strategies may mitigate secondary injury or enhance symptom control, they do not directly address the multifactorial biological signaling regulating nerve regeneration. As a result, treatment outcomes remain variable, and no universally accepted regenerative treatment has emerged for daily clinical application.

Recently, regenerative peptides have garnered attention as promising biologic regulators of tissue healing and neural regeneration. Contrary to traditional treatments that target isolated components of the injury pathway, numerous peptide-mediated agents demonstrate pleiotropic activities that affect several regenerative cascades concurrently. Preclinical studies suggest that Body Protection Compound-157 (BPC-157) may enhance cytoprotection, endothelial stability, and angiogenesis while regulating inflammatory pathways. Similarly, TB-500, a derivative of thymosin β4, has been associated with enhanced cellular migration, cytoskeletal remodeling, and tissue healing in experimental models. ARA-290 has shown tissue-protective and immunoregulatory features in preclinical and selected early clinical studies. Nonetheless, these mechanisms have not been directly shown in patients with IAN injury and should be regarded as biologically plausible hypotheses rather than established clinical mechanisms.

A recent case report published in Frontiers in Oral Health presents three clinical cases of IAN injury managed with a multimodal peptide-mediated approach comprising peptide agents, adjunctive dexamethasone, and local anesthesia. The first case involved a 38-year-old female with a prior history of Le Fort orthognathic surgery who experienced failure of a dental implant at site #30, related to cyst formation, localized bone necrosis, and abscess formation. Within 24 hours after reimplantation, she reported right-sided mandibular paresthesia. CBCT imaging revealed that the implant was placed in proximity to the IAN canal, nearly 2 mm away, without direct canal violation. The clinical findings were consistent with an indirect IAN injury, possibly associated with compression, edema, or local inflammatory responses rather than direct nerve transection.

The second case involved an 85-year-old patient who experienced failure of a dental implant at site #30. The implant was extracted utilizing a trephine bur, and the osteotomy site was grafted with platelet-rich fibrin. Within 24 hours post-surgery, the patient reported right-sided mandibular paresthesia extending from the chin to the ipsilateral oral commissure. CBCT imaging showed that the osteotomy site was in proximity to the IAN canal, around 2 mm away, with no indication of direct canal penetration. The observations indicated a compression-associated or indirect IAN injury. The third case involved a 48-year-old female who presented after extraction of a tooth and subsequent bone grafting in the right posterior mandible. Postoperatively, she reported enduring numbness on the right side of the mandible, affecting the lower lip and chin. Periapical and panoramic radiographs showed tooth-related pathology directly associated with the IAN canal before extraction, reflecting a potentially more severe injury pattern.

All three patients received weekly localized intraoral submucosal infiltrations over a period of 4 weeks, utilizing the same multimodal protocol consisting of peptide agents (ARA-290 [4 mg], TB-500 [10 mg], and BPC-157 [1 mg]) together with dexamethasone (8 mg) and bupivacaine 0.5% with 1:200,000 epinephrine (3.6 mL). Injections were precisely targeted to the affected sensory distribution. During follow-up, all three patients reported gradual enhancement in neurosensory symptoms. In the first case, the previously documented area of paresthesia had substantially decreased, with only a minor residual region of hypoesthesia (almost 3 mm) persisting inferior to the vermilion border of the lower lip. In the second case, the paresthetic region had significantly diminished in size, with only a minor residual area of diminished sensation (nearly 2 mm) persisting at the lateral aspect of the chin. In the third case, the subjective numbness had diminished by nearly 95%, with almost complete resolution of the affected region. A six-month follow-up revealed satisfactory hard tissue repair, and functional recovery was adequate to enable the placement of dental implants in the previously affected area without complications. No treatment-associated adverse events were documented in any of the three cases.

Despite these promising findings, numerous alternative interpretations must be considered. Spontaneous recovery is a well-established phenomenon after minor IAN injury, especially in instances of limited axonotmesis and neuropraxia. Hence, it remains indeterminate to what extent the documented recovery was due to intervention rather than the inherent healing trajectory. Additionally, the multimodal essence of the approach impedes the detection of the contribution of any singular element. The observable advantages may stem from one agent, a subset of agents, or associations among several treatments. The likelihood of observer bias and placebo effects must also be recognized, especially since outcome evaluation depended mainly on clinical assessment and patient-documented sensory enhancements. Since this was an uncontrolled observational case series, these outcomes should not be interpreted as evidence of intervention efficacy. Spontaneous recovery, placebo effects, regression to the mean, variability in injury severity, and the simultaneous use of dexamethasone and local anesthetic all represent plausible alternative explanations for the observed clinical course.

Many limitations require recognition. The limited sample size, absence of a control group, and non-randomized treatment allocation are significant constraints. An additional limitation is the absence of standardized quantitative neurosensory evaluation. Recovery was mainly assessed using routine clinical examination, patient-reported changes in sensation, and serial photographic documentation. Objective examinations, such as validated patient-reported outcome measures, visual analog pain scores, electrophysiological studies, quantitative sensory testing, thermal discrimination, pin-prick testing, two-point discrimination, and static light-touch testing, were not obtained prospectively. Hence, the magnitude of sensory recovery cannot be objectively quantified or directly compared with other published studies using standardized neurosensory outcome measures. Another important limitation is the inability to isolate the effects of the peptide components from those of adjunctive therapy. All three patients received an identical multimodal protocol, making it impossible to determine whether the observed clinical course resulted from one agent, a combination of agents, associations among interventions, or the expected natural history of recovery. Moreover, follow-up duration was inconsistent, restricting evaluation of long-term stability. Furthermore, the long-term safety profiles, pharmacokinetics, optimal dosing approaches, and regulatory status of many peptide-mediated agents remain inadequately characterized.

Future investigations should emphasize prospective controlled trials assessing peptide-mediated regenerative approaches in patients with well-characterized IAN injuries. Longer follow-ups, imaging-dependent evaluation, quantitative sensory assessments, and standardized neurosensory outcome measures will be required to identify whether these interventions offer a significant advantage beyond traditional management and spontaneous healing. Finally, comparative studies assessing isolated versus combination peptide interventions may facilitate clarifying potential synergistic impacts and determining optimal therapeutic strategies. The present study describes three patients with IAN injury who experienced neurosensory recovery during follow-up after receiving a multimodal peptide-mediated protocol. Because of the uncontrolled observational design, lack of randomization, blinding, standardized neurosensory evaluation, and untreated controls, these findings should not be interpreted as evidence of treatment efficacy or causality. Rather, these cases represent hypothesis-generating clinical observations that support further prospective controlled trials assessing the biological rationale and potential role of regenerative peptide-mediated strategies in the management of IAN injury.

Subject of Research: Regenerative peptides as adjuncts for inferior alveolar nerve injury repair

Article Title: Case Report: Regenerative peptides for Inferior alveolar nerve injury: a narrative review with hypothesis-generating three clinical cases

Article References: Froum, S., Estrin, N., Pico, G., Yakubov, M., Ahmad, P., & LaValle, J. (2026). Case Report: Regenerative peptides for Inferior alveolar nerve injury: a narrative review with hypothesis-generating three clinical cases. Frontiers in Oral Health, 7, Article 1907109. https://doi.org/10.3389/froh.2026.1907109

Image Credits: AI Generated

DOI: 10.3389/froh.2026.1907109

Keywords: inferior alveolar nerve, regenerative peptides, BPC-157, TB-500, ARA-290, nerve regeneration, oral and maxillofacial surgery, dental implants, case report, neurosensory recovery, Case, Report